start-ver=1.4 cd-journal=joma no-vol=384 cd-vols= no-issue= article-no= start-page=1028 end-page=1037 dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210318 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis.
Methods
We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed.
Results
Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy–Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group.
Conclusions
Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549. opens in new tab.) en-copyright= kn-copyright= en-aut-name=HillmenPeter en-aut-sei=Hillmen en-aut-mei=Peter kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SzerJeff en-aut-sei=Szer en-aut-mei=Jeff kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WeitzIlene en-aut-sei=Weitz en-aut-mei=Ilene kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=RöthAlexander en-aut-sei=Röth en-aut-mei=Alexander kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HöchsmannBritta en-aut-sei=Höchsmann en-aut-mei=Britta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=PanseJens en-aut-sei=Panse en-aut-mei=Jens kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UsukiKensuke en-aut-sei=Usuki en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=GriffinMorag en-aut-sei=Griffin en-aut-mei=Morag kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KiladjianJean-Jacques en-aut-sei=Kiladjian en-aut-mei=Jean-Jacques kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=de CastroCarlos en-aut-sei=de Castro en-aut-mei=Carlos kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NishimoriHisakazu en-aut-sei=Nishimori en-aut-mei=Hisakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TanLisa en-aut-sei=Tan en-aut-mei=Lisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HamdaniMohamed en-aut-sei=Hamdani en-aut-mei=Mohamed kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=DeschateletsPascal en-aut-sei=Deschatelets en-aut-mei=Pascal kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FrancoisCedric en-aut-sei=Francois en-aut-mei=Cedric kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=GrossiFederico en-aut-sei=Grossi en-aut-mei=Federico kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AjayiTemitayo en-aut-sei=Ajayi en-aut-mei=Temitayo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=RisitanoAntonio en-aut-sei=Risitano en-aut-mei=Antonio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=Peffault de la TourRégis en-aut-sei=Peffault de la Tour en-aut-mei=Régis kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=the Department of Haematology, St. James’s University Hospital kn-affil= affil-num=2 en-affil=the Department of Clinical Haematology, Peter MacCallum Cancer Center and Royal Melbourne Hospital kn-affil= affil-num=3 en-affil=Jane Anne Nohl Division of Hematology, Keck School of Medicine of USC kn-affil= affil-num=4 en-affil=the Department of Hematology, West German Cancer Center University Hospital Essen, University of Duisburg-Essen kn-affil= affil-num=5 en-affil=the Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service and University Hospital Ulm kn-affil= affil-num=6 en-affil=the Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen kn-affil= affil-num=7 en-affil= the Department of Hematology, NTT Medical Center Tokyo kn-affil= affil-num=8 en-affil=the Department of Haematology, St. James’s University Hospital kn-affil= affil-num=9 en-affil=Centre d’Investigations Cliniques, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Université de Paris kn-affil= affil-num=10 en-affil=the Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University kn-affil= affil-num=11 en-affil=the Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=12 en-affil=Lisa Tan Pharma Consulting kn-affil= affil-num=13 en-affil=Apellis Pharmaceuticals kn-affil= affil-num=14 en-affil=Apellis Pharmaceuticals kn-affil= affil-num=15 en-affil=Apellis Pharmaceuticals kn-affil= affil-num=16 en-affil=Apellis Pharmaceuticals kn-affil= affil-num=17 en-affil=Apellis Pharmaceuticals kn-affil= affil-num=18 en-affil=the Hematology and BMT Unit, AORN San Giuseppe Moscati kn-affil= affil-num=19 en-affil=the French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Université de Paris kn-affil= END